Capecitabine As First-Line Treatment for Patients Older Than 70 Years With Metastatic Colorectal Cancer: An Oncopaz Cooperative Group Study
http://www.100md.com
《临床肿瘤学》
the Hospital La Paz de Madrid
Hospital Puerta del Mar de Cadiz, Madrid
Hospital Clinico de Zaragoza, Zaragoza
Hospital Cruz Roja de Barcelona, Barcelona
Hospital San Pedro de Alcántara de Cáceres, Cáceres
Hospital General Universitario de Valencia, Valencia
Hospital Obispo Polanco de Teruel, Teruel
Hospital San Jorge de Huesca, Huesca
Hospital Universitario de Santiago de Compostela, Santiago de Compostela
Hospital Virgen de la Salud de Toledo, Toledo, Spain
ABSTRACT
PURPOSE: To determine the tolerability of capecitabine in elderly patients with advanced colorectal cancer (CRC).
PATIENTS AND METHODS: Fifty-one patients with advanced CRC who were 70 years and considered ineligible for combination chemotherapy received oral capecitabine 1,250 mg/m2 twice daily on days 1 to 14 every 3 weeks. Patients with a creatinine clearance of 30 to 50 mL/min received a dose of 950 mg/m2 twice daily.
RESULTS: A total of 248 cycles of capecitabine were administered (median, five cycles; range, one to eight cycles). The overall response rate was 24% (95% CI, 15% to 41%), including two complete responses (CR; 4%) and 10 partial responses (PR; 20%). Disease control (CR + PR + stable disease) was achieved in 67% of patients. The median times to disease progression and overall survival were 7 months (95% CI, 6.4 to 9.5 months) and 11 months (95% CI, 8.6 to 13.3 months), respectively. Of the 35 patients evaluated for clinical benefit response, 14 (40%; 95% CI, 24% to 58%) showed clinical benefit. Capecitabine was well tolerated. Treatment-related grade 3 and 4 adverse events were observed in only six patients (12%), and the most common events were diarrhea, hand-foot syndrome, and thrombocytopenia. One patient (2%) had an episode of angina, but no treatment-related deaths were reported.
CONCLUSION: Our findings suggest that capecitabine is effective and well tolerated in elderly patients with advanced CRC who are considered ineligible for combination chemotherapy.
INTRODUCTION
Colorectal cancer (CRC) is one of the most frequently encountered malignancies and is third behind breast and cervical cancer in women and fourth after lung, stomach, and prostate cancer in men.1 The prevalence of CRC increases significantly with age, with 40% of patients in Europe being older than 74 years of age at the time of initial diagnosis.2 Considering that approximately 25% of the population in industrialized countries is older than 70 years, the number of elderly patients with CRC is expected to increase significantly over the next two decades.
For more than 40 years, fluorouracil (FU) has been the mainstay of chemotherapy for advanced CRC. Recently, however, the topoisomerase I inhibitor irinotecan and the platinum compound oxaliplatin have shown efficacy as second-line single-agent therapy and as first-line therapy in combination with fluoropyrimidines. In large phase III trials, irinotecan in combination with FU-leucovorin and oxaliplatin in combination with FU-LV showed superior efficacy compared with FU-LV alone as first-line therapy.3-7 Although such combination regimens offer important improvements over FU-LV alone, they are often limited by high rates of toxicity,8,9 the inconvenience and discomfort of regular hospital visits for intravenous (IV) drug administration, and an increased associated risk of infection and thromboembolism.10-12 These issues are a particular problem in the elderly. Although the aging process is highly individualized, we considered 70 years of age as a chronologic cutoff for the onset of senescence because the rate of age-related changes increases steeply after this age.13 The progressive restriction in the functional reserve of various organ systems, the increasing prevalence of comorbid conditions, and the fear of greater susceptibility to side effects that negatively impact quality of life may be some of the factors that account for the reluctance to use chemotherapy in the elderly.14,15 Because the number of people older than 70 years included in clinical trials is small, the potential benefits and tolerability of combination chemotherapy in elderly patients remains unclear.
Capecitabine (Xeloda; Hoffmann-La Roche Inc, Nutley, NJ) is an orally administered fluoropyrimidine designed to deliver FU to tumor tissue.16,17 Capecitabine single-agent therapy has been shown to be highly effective as first-line treatment for metastatic CRC, demonstrating superior response rates and at least equivalent time to progression (TTP) and survival compared with FU-LV in two large, randomized, controlled phase III trials.18-20 An integrated analysis of safety from these trials, which included a total of 596 patients treated with capecitabine, also demonstrated a significantly lower rate of grade 3 and 4 diarrhea, stomatitis, nausea, and neutropenia but a higher rate of hand-foot syndrome with capecitabine.21 In the joint safety analysis, 51 patients were between 75 and 79 years of age, and only 13 patients were 80 years. Although a higher rate of adverse events was observed in the oldest patients, this could be attributable to the deterioration of renal function with age. A joint analysis of results from studies of irinotecan-FU-LV versus FU-LV3 and FU-LV versus capecitabine18 has also shown that administration of capecitabine single-agent therapy could be more cost effective than irinotecan-FU-LV in patients more than 65 years of age.22
The efficacy, favorable tolerability, and ease of administration of capecitabine make it ideal for use in both the general CRC population and in elderly patients. Consequently, the primary objective of this study was to determine the safety profile and to identify the possible predictive factors for toxicity when capecitabine single-agent therapy was administered in patients with advanced CRC who were 70 years.
PATIENTS AND METHODS
Patient Population
April 2002 to November 2002, 51 patients 70 years with recurrent or metastatic CRC were enrolled. All patients had measurable disease defined by the presence of at least one unidimensionally measurable lesion (Response Evaluation Criteria in Solid Tumors criteria)23 by computed tomography scan. Pleural effusion, ascites, osteoblastic lesions, or previously irradiated lesions were not accepted as measurable disease.
Patients who had received prior adjuvant FU-based chemotherapy were eligible if they had been disease-free for at least 6 months after the completion of therapy. Patients who had received radiotherapy were eligible if there was at least one measurable lesion outside the radiation field. Other inclusion criteria were as follows: Eastern Cooperative Oncology Group (ECOG) performance status 2; life expectancy of at least 3 months; determined as unsuitable for combination chemotherapy by their doctor or refusal of treatment by the patient; adequate hematologic function (granulocyte count 2 x 109/L and platelets > 100 x 109/L); adequate hepatic function (serum bilirubin < 1.25 x upper normal limit [UNL] and AST and ALT values < 2.5 x UNL in the absence of hepatic metastases or < 5 x UNL in the presence of metastasis); and adequate renal function (creatinine clearance 30 mL/min). All patients provided written informed consent according to local ethical committee directives.
Patients with operable metastatic disease were excluded from the study. Other exclusion criteria were as follows: clinically significant cardiac disease or myocardial infarction within the last 12 months; lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome; prior chemotherapy for advanced disease; known brain or meningeal metastases; and history of other malignancy, except basal cell carcinoma or adequately treated in situ cervical carcinoma.
Treatment Plan
The initial dose of capecitabine depended on the renal function of the patient, as determined by creatinine clearance. Patients with a creatinine clearance of more than 50 mL/min received capecitabine at 1,250 mg/m2 twice daily (2,500 mg/m2 total daily dose) for 2 weeks followed by 1 week of rest. In patients with a creatinine clearance of 30 to 50 mL/min, the dose of capecitabine was reduced to 950 mg/m2 twice daily (1,900 mg/m2 total daily dose). The dose of capecitabine was rounded to the next closest dose that could be administered using a combination of 500- and 150-mg tablets. The two daily doses of capecitabine were administered 12 ± 2 hours apart, 30 minutes after meals (breakfast and evening meal), with approximately 200 mL of water.
The Cockcroft-Gault formula24 was used to calculate the creatinine clearance between cycles. If clearance was less than 30 mL/min, treatment was interrupted. Cycles were repeated every 3 weeks for a minimum of three cycles per patient, unless disease progression was detected. Patients with a partial response or stable disease continued chemotherapy until progression or the development of unacceptable adverse events.
Patients were evaluated for adverse events before each cycle and graded according to WHO criteria.25 For hand-foot syndrome, the following grading system was used26: grade 1, numbness, dysesthesia, painless swelling, or erythema not disrupting normal activities; grade 2, painful erythema and/or swelling or symptoms affecting activities of daily living; and grade 3, moist desquamation, ulceration, blistering, and/or severe pain or symptoms making patients unable to work or perform activities of daily living. Treatment was continued at the same dose (without interruption or dose reduction) in case of grade 1 adverse events. Capecitabine dose reduction was not required after the first appearance of any grade 2 adverse events, although treatment was interrupted until the event had resolved to grade 0 or 1. Treatment was interrupted and the capecitabine dose was reduced by 25% in patients who experienced a second occurrence of a given grade 2 adverse event or any grade 3 event, and capecitabine dose was reduced by 50% for patients who experienced a third occurrence of a given grade 2 adverse event or the second occurrence of a given grade 3 adverse event. Treatment was discontinued in the case of grade 4 adverse events or if a given event occurred at grades 2 or 3 despite dose reduction to 50% of the original dose.
Pretreatment and Follow-Up Evaluation
A diagnostic work-up was performed within 3 weeks before the start of treatment and consisted of a complete clinical history, physical examination, blood analysis (hematology and complete biochemistry), and imaging studies as needed (chest x-ray, computed tomography of the chest, abdomen and pelvis, abdominal ultrasound, and bone scan). The Charlson comorbidity scale,27 and the Katz et al28 and Lawton29 Activities of Daily Living (ADL) indices were used in patient assessment. Patients' ECOG performance status and weight were also recorded. An ECG was performed in all patients before receiving study treatment. Symptom assessment, physical examination, and blood biochemistry were repeated before each treatment cycle. Tumor measurements were taken every three cycles or sooner if clinically indicated.
Response Criteria
Patients were evaluated clinically on an intent-to-treat basis at least every 3 weeks and radiographically every 9 weeks. The same evaluation modality was used throughout the study. Response Evaluation Criteria in Solid Tumors response guidelines were used,23 defining all responses after at least 9 weeks of therapy as follows: complete response (CR), partial response (PR), stable disease (SD), or progressive disease. We defined disease control as the sum of patients achieving a CR, PR, or SD. Confirmation of all responses was required after 4 weeks. TTP was estimated from the date of the first course of treatment to the date of the first documentation of disease progression. Survival was calculated by the same method from the date of the first cycle of treatment until the date of death or last known follow-up.
Clinical Benefit Response
An assessment of clinical benefit was determined from a composite of pain intensity, analgesic consumption, ECOG performance status, and the presence of anorexia and asthenia. The same doctor for each patient assessed ECOG performance status and symptoms before each chemotherapy cycle. Patients entered a pain stabilization run-in period to establish baseline measures. Pain was assessed with the Memorial Pain Assessment Card (MPAC).30 Asthenia and anorexia were assessed using a line-of-vision visual analog scale (VAS) of 0 to 100. In addition, patients' weight was measured at each visit. Patients were considered to be assessable for palliative benefits when they initially had one of the following signs or symptoms: an ECOG performance status 1, an MPAC score 20, baseline analgesic consumption of 10 morphine equivalents mg/d, score on the line-of-vision VAS for anorexia and/or asthenia of 20, or weight loss more than 10% during the previous 6 months.
Symptom improvement was defined as follows: an improvement of at least one score from baseline in ECOG performance status; 5% weight gain from baseline (patients with edema, ascites, or pleural effusion were excluded from this category); or an improvement of 50% from baseline in disease-related symptoms (pain, use of analgesics, anorexia, and asthenia) and analgesic consumption (measured weekly in morphine-equivalent milligrams). Each of these improvements had to be sustained for at least 4 weeks.31 Clinical benefit was defined as improvement in ECOG performance status without worsening of symptoms or weight loss, weight increase without worsening of ECOG performance status or symptoms, or symptom improvement without worsening of ECOG performance status.
Statistical Methods
The primary end point of the trial was to determine the safety profile of capecitabine. Secondary objectives were clinical benefit, TTP, and survival. Dose-intensity was calculated for each patient from the total dose of capecitabine administered during the entire course of treatment and expressed as the mean drug dose in mg/m2/wk. It was anticipated that 17% of patients would develop grade 3 or 4 toxicity.21 Therefore, 51 patients had to be included to estimate toxicity within a 20% maximum limit for the 95% CI. Univariate analysis was used to compare the rate of grade 3 and 4 adverse events according to age (70 to 79 years v 80 years), sex, creatinine clearance (< 50 mL/min v 50 mL/min), Charlson comorbidity scale (0 v 1), ECOG performance status (0 v 1), and Instrumental ADL (IADL) and ADL (independent v dependent). Wilcoxon's signed rank test (to compare the quantitative variables) and Fisher's exact test (to compare percentages) were used. Survival time and TTP were calculated using the Kaplan-Meier method.
RESULTS
Patient Characteristics
A total of 51 patients 70 years with advanced CRC were enrolled. The characteristics of the patients are listed in Table 1. Thirteen patients (25%) presented with metastases at the time of diagnosis, and in eight patients (16%), the primary tumor was not resected. The 39 remaining patients (76%) presented with secondary metastases to a previously resected tumor. Of these patients, 10 (26%) had received previous adjuvant chemotherapy, and eight (20%) had been treated with chemotherapy and radiotherapy.
Thirteen patients had previously refused treatment with combination chemotherapy. In the remaining patients, combination regimens were not used because of poor functional status (as defined by serious dependency in the ADL scale or in the IADL scale, n = 15; comorbidities, n = 5; and because of age older than 75 years, n = 18).
Comorbid conditions are listed in Table 2. When interpreting these results, it is important to note that the Charlson's scale only picks up serious conditions that have an impact on treatment decisions. Other less serious comorbid conditions, such as hypertension or gastric ulcers, are not included.
Treatment Duration
A total of 248 cycles of treatment were administered, with a median of five cycles per patient (range, one to eight cycles). Nine patients (18%) received less than three cycles of capecitabine; five patients (10%) received less than three cycles because of disease progression, two patients (4%) received less than three cycles because of adverse events, and one patient (2%) refused to continue treatment. Nevertheless, all of the patients enrolled were considered assessable for both efficacy and safety. Twenty-three patients (45%) experienced treatment delays during the study (14 patients for causes unrelated to the treatment, two because of neutropenia, and seven because of nonhematologic adverse events). The median dose intensity was 10.3 g/m2/wk, which is equivalent to 88% of the predicted dose intensity.
Tumor Response and Survival
In the intent-to-treat analysis, the overall response rate was 24% (95% CI, 15% to 41%), including two patients (4%) with a CR and 10 patients (20%) with a PR. Twenty-two patients (43%) maintained SD, and 17 patients (33%) had disease progression. Overall, disease control (CR + PR + SD) was achieved in 67% of the patients. There was no relationship between the rate of response and the location of metastases, ECOG performance status, ADL, IADL, or patient age.
The median TTP was 7 months (95% CI, 6.4 to 9.5 months; Fig 1). Median survival was 11 months (95% CI, 8.6 to 13.3 months; Fig 2), and the actuarial survival rate per year was 40%.
Clinical Benefit Response
Of the 51 enrolled patients, 35 were assessable for a clinical benefit response. The remaining 16 patients were not assessable because of the following: ECOG of 0, MPAC score less than 20, or VAS for anorexia and asthenia of less than 20. Clinical benefit responses are listed in Table 3. Overall, 14 patients (40%; 95% CI, 24% to 58%) had a clinical benefit. The median duration of clinical benefit was 4 months (95% CI, 2 to 8 months).
Safety
Generally, treatment was well tolerated. Twenty-eight patients (55%) experienced treatment-related adverse events, the majority of which were grade 1 to 2 in severity. The main treatment-related adverse events were gastrointestinal and hematologic (Fig 3). Six patients (12%) experienced treatment-related grade 3 and 4 adverse events; one patient (2%) had nausea and vomiting, three (6%) had diarrhea, three (6%) had hand-foot syndrome, one (2%) had neutropenia, and two (4%) had thrombocytopenia. One patient (2%) experienced one episode of angina. No treatment-related deaths were reported during the study.
In an exploratory univariate analysis, we detected no relationship between the presence of grade 3 and 4 adverse events and patient age (70 to 79 years v 80 years), sex, IADL, ADL, ECOG, comorbidity, renal function, or capecitabine dose (950 mg/m2 twice a day or 1,250 mg/m2 twice a day). However, it should be noted that, because of the low rate of grade 3 and 4 adverse events and the small sample size, the study did not have sufficient power to definitely rule out any such relationships.
DISCUSSION
Age clearly represents a barrier to the inclusion of patients in clinical trials of new cancer therapies.32,33 In the most relevant studies performed in patients with CRC, less than 20% of patients were 70 years.34 In addition, the number of patients older than 75 years is low, suggesting that these patients are carefully selected and are not necessarily representative of this age group. Therefore, extrapolating the results from clinical trials including young patients or selected elderly populations to groups over the age of 75 years is problematic.
In the current study, we evaluated capecitabine as first-line therapy in elderly patients with advanced CRC who were considered ineligible for combination chemotherapy. The patients included in the study were typical of an elderly population because the proportion of patients with rectal cancer was higher than normal (47%), which tends to be the case in older patients. Furthermore, the fact that only 46% of the patients potentially eligible for adjuvant chemotherapy had received prior adjuvant chemotherapy and adjuvant treatment was not administered to 34% of the patients with stage III disease provides further proof that elderly patients are often undertreated in the adjuvant setting.
In our study, capecitabine produced a response rate of 24%, a median TTP of 7 months, and a median survival of 11 months. These findings are similar to those reported from previous studies of capecitabine as first-line therapy in patients of all ages with advanced CRC.20 Although TTP in our study seemed to be longer compared with previously published findings with capecitabine single-agent therapy or similar to the capecitabine-based combinations,20,35,36 this may have been the result of tumor evaluation every 9 weeks instead of every 6 weeks as in previous studies. In contrast, median overall survival time was a little shorter than reported for capecitabine single-agent therapy in the first-line setting. However, this might be explained by the baseline characteristics of our elderly patients and the fact that they were ineligible to receive combination chemotherapy, which would be expected to lead to a median survival time of more than 12 months.
The safety of capecitabine in the current study was favorable, with only 12% of patients developing grade 3 and 4 adverse events. This is likely to be attributable to the adjustment of the dose based on patients' creatinine clearance.21,37 These results are similar to those of another study in which capecitabine at a dosage of 1,000 mg/m2 twice daily led to a grade 3 and 4 adverse event rate of 14% in elderly and less fit patients with advanced CRC.38 Alternatively, the fact that 35% of the patients enrolled onto the study had received prior chemotherapy with FU-LV in the adjuvant setting with a good tolerance could have introduced a bias in the sense that these patients might also have good tolerance to capecitabine. Importantly, we did not find any correlation between the occurrence of adverse events and baseline characteristics that are normally associated with increased toxicity, such as female sex,39 the presence of comorbidities,15 performance status, and so on. In particular, excessive comorbidity has been reported to be associated with increased toxicity in elderly patients.15 Despite 80% of the patients in our study suffering from some comorbidity and 29% of the patients being 80 years, we did not detect any higher rate of adverse events in these patients. However, it is necessary to note that the power of the study, because of the low number of patients with severe adverse events, might be insufficient to detect such a relationship.
In addition to its good antitumor efficacy and favorable tolerability, oral administration of capecitabine avoids the possible complications and discomfort of IV therapy.8-12 Furthermore, compared with weekly or biweekly IV dosing schedules, home-based administration of capecitabine on days 1 to 14 every 3 weeks reduces the need for hospital visits, which may be inconvenient in elderly patients who require assistance from a relative or caregiver. Nevertheless, it is still important for patients to receive good-quality educational materials and to have regular phone contact with their nurse or physician. Patients with dependency for the daily activities of life may still require a caregiver who takes full responsibility of administering treatment and the early detection of adverse events.
Combination chemotherapy is currently considered to be more effective than single-agent therapy in patients with advanced CRC, and therefore, it is important to consider to what extent elderly patients should receive combination regimens. Because the elderly represent a heterogeneous population, treatment should be individualized based on the possible risks and benefits expected in each patient. In addition, it is important to take into account the patient's wishes; although older patients are often as willing to chose combination chemotherapy as their younger counterparts, the elderly require a greater survival advantage before choosing a more toxic regimen over a less-aggressive alternative.40 When choosing a combination regimen, it is important to consider that the patient's age can affect the pharmacokinetics of certain drugs like irinotecan.34 Indeed, a higher rate of adverse events was detected in a study of irinotecan in patients 65 years compared with patients younger than 65 years (rate of grade 3 and 4 diarrhea, 39% v 19%, respectively),41 although this has not been confirmed in other studies.42 An increase in grade 3 and 4 diarrhea has also been reported when oxaliplatin is administered in combination with FU-LV in patients older than 65 years (18% v 8% in patients aged 65 years).5 Nevertheless, physiologic factors rather than actual age govern treatment decisions, and there is still a huge population of patients who are unable to tolerate combinations of cytotoxic agents.
Clearly, as supported by the results of our study, capecitabine single-agent therapy is an important therapeutic option in elderly patients who are ineligible for combination chemotherapy. The availability of new biologic therapies, such as bevacizumab (Avastin; Genentech, South San Francisco, CA), which has already shown promising activity and good tolerability in combination with FU in advanced CRC and with capecitabine in advanced breast cancer,43,44 might be expected to improve outcomes without increasing toxicity in elderly patients. A study combining capecitabine with bevacizumab in elderly patients with advanced CRC is an interesting possibility for the future. The apparent lack of sufficient adjuvant therapy for elderly patients with early-stage colon cancer is another important area where a drug like capecitabine, which has a proven safety profile in the metastatic and adjuvant settings,45 can improve outcomes in an increasingly elderly patient population.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by Hoffmann-La Roche Inc, Nutley, NJ.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Ferlay J, Bray F, Pisani P, et al: GLOBOCAN 2000: Cancer Incidence, Mortality and Prevalence Worldwide, Version 1.0. Lyon, France, International Agency for Research on Cancer CancerBase No. 5, IARCPress, 2001
Gatta G, Faivre J, Capocaccia R, et al: Survival of colorectal cancer patients in Europe during the period 1978-1989: EUROCARE Working Group. Eur J Cancer 34:2176-2183, 1998
Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan Study Group. N Engl J Med 343:905-914, 2000
Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomized trial. Lancet 355:1041-1047, 2000
de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000
Giacchetti S, Perpoint B, Zidani R, et al: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18:136-147, 2000
Grothey A, Deschler B, Kroening H, et al: Phase III study of bolus 5-fluorouracil (5-FU)/folinic acid (FA) (Mayo) vs weekly high-dose 24h 5-FU infusion/FA + oxaliplatin (OXA) (FUFOX) in advanced colorectal cancer (ACRC). Proc Am Soc Clin Oncol 21:129a, 2002 (abstr 512)
Ledermann JA, Leonard P, Seymour M: Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer. N Engl J Med 345:145-146, 2001
Rothenberg ML, Meropol NJ, Poplin EA, et al: Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: Summary findings of an independent panel. J Clin Oncol 19:3801-3807, 2001
Clark DR, Raffin TA: Infectious complications of indwelling long-term central venous catheters. Chest 97:966-972, 1990
Prandoni P, Bernardi E: Upper extremity deep vein thrombosis. Curr Opin Pulm Med 5:222-226, 1999
Verso M, Agnelli G: Venous thromboembolism associated with long-term use of central venous catheters in cancer patients. J Clin Oncol 21:3665-3675, 2003
Balducci L, Extermann M: Cancer and aging: An evolving panorama. Hematol Oncol Clin North Am 14:1-16, 2000
Simmonds PD, Best LY: Should chemotherapy be used as a treatment of advanced colorectal carcinoma (ACC) in patients over 70 years age Contra. Eur J Cancer 35:1640-1649, 1999
Balducci L, Extermann M: Management of cancer in the older person: A practical approach. Oncologist 5:224-237, 2000
Miwa M, Ura M, Nishida M, et al: Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34:1274-1281, 1998
Schüller J, Cassidy J, Dumont E, et al: Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 45:291-297, 2000
Hoff PM, Ansari R, Batist G, et al: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 19:2282-2292, 2001
Van Cutsem E, Twelves C, Cassidy J, et al: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: Results of a large phase III study. J Clin Oncol 19:4097-4106, 2001
Van Cutsem E, Hoff PM, Harper P, et al: Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: Integrated efficacy data and novel analyses from two large, randomized, phase III trials. Br J Cancer 90:1190-1197, 2004
Cassidy J, Twelves C, Van Cutsem E, et al: First-line oral capecitabine therapy in metastatic colorectal cancer: A favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann Oncol 13:566-575, 2002
Vincent M, Jonker D, Lane Ilersich A: A model for assessing cost-effectiveness of metastatic colorectal chemotherapy. Proc Am Soc Clin Oncol 20:211b, 2001 (abstr 2595)
Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000
Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41, 1976
World Health Organization: WHO Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, World Health Organization, WHO offset publication No. 48, 1979
Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17:485-493, 1999
Charlson ME, Pompei P, Ales KL, et al: A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis 40:373-383, 1987
Katz S, Ford AB, Moskowitz RW, et al: Studies of illness in the aged: The index of ADL—To standardized measure of biological and psychosocial function. JAMA 185:914-919, 1963
Lawton MP: Scales to measure competence in everyday activities. Psychopharmacol Bull 24:609-614, 1988
Fishman B, Pasternak S, Wallestein SL, et al: The Memorial pain assessment card: A valid instrument for the evaluation of cancer pain. Cancer 60:1151-1158, 1987
Cocconi G, Cunningham D, Van Cutsem E, et al: Open, randomized multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. J Clin Oncol 16:2943-2952, 1998
Yee KW, Pater JL, Pho L, et al: Enrollment of older patients in cancer treatment trials in Canada: Why is age a barrier J Clin Oncol 21:1618-1623, 2003
Lewis JH, Kilgore ML, Goldman DP, et al: Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol 21:1383-1389, 2003
Honecker F, Kohne CH, Bokemeyer C: Colorectal cancer in the elderly: Is palliative chemotherapy of value Drugs Aging 20:1-11, 2003
Shields AF, Zalupski MM, Marshall JL, et al: Treatment of advanced colorectal carcinoma with oxaliplatin and capecitabine: A phase II trial. Cancer 100:531-537, 2004
Cassidy J, Tabernero J, Twelves C, et al: XELOX (capecitabine plus oxaliplatin): Active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 22:2084-2091, 2004
Gieschke R, Burger HU, Reigner B, et al: Population pharmacokinetics and concentration-effect relationships of capecitabine metabolites in colorectal cancer patients. Br J Clin Pharmacol 55:252-263, 2003
Vincent M, Jonker D, Kerr I, et al: Reduced-dose capecitabine monotherapy in older or less fit patients with advanced colo-rectal cancer (A CR Ca). Proc Am Soc Clin Oncol 22: 323, 2003 (abstr 1297)
Macdonald JS: Vive la difference: Sex and fluorouracil toxicity. J Clin Oncol 20:1439-1441, 2002
Yellen SB, Cella DF, Leslie WT: Age and clinical decision making in oncology patients. J Natl Cancer Inst 86:1766-1770, 1994
Rothenberg ML, Cox JV, DeVore RF, et al: A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer 85:786-795, 1999
Rougier P, Mitry E, Cunningham D, et al: Is age a prognostic factor of toxicity and efficacy in patients (pts) with metastatic colorectal cancer (MCRC) receiving irinotecan in combination with 5FU/folinic acid (FA). Proc Am Soc Clin Oncol 22: 267, 2003 (abstr 1072)
Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al: Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60-65, 2003
Miller KD, Chap LI, Holmes FA, et al: Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792-799, 2005
Scheithauer W, McKendrick J, Begbie S, et al: Oral capecitabine as an alternative to i.v. 5-fluorouracil-based adjuvant therapy for colon cancer: Safety results of a randomized, phase III trial. Ann Oncol 14:1735-1743, 2003(Jaime Feliu, Pilar Escude)
Hospital Puerta del Mar de Cadiz, Madrid
Hospital Clinico de Zaragoza, Zaragoza
Hospital Cruz Roja de Barcelona, Barcelona
Hospital San Pedro de Alcántara de Cáceres, Cáceres
Hospital General Universitario de Valencia, Valencia
Hospital Obispo Polanco de Teruel, Teruel
Hospital San Jorge de Huesca, Huesca
Hospital Universitario de Santiago de Compostela, Santiago de Compostela
Hospital Virgen de la Salud de Toledo, Toledo, Spain
ABSTRACT
PURPOSE: To determine the tolerability of capecitabine in elderly patients with advanced colorectal cancer (CRC).
PATIENTS AND METHODS: Fifty-one patients with advanced CRC who were 70 years and considered ineligible for combination chemotherapy received oral capecitabine 1,250 mg/m2 twice daily on days 1 to 14 every 3 weeks. Patients with a creatinine clearance of 30 to 50 mL/min received a dose of 950 mg/m2 twice daily.
RESULTS: A total of 248 cycles of capecitabine were administered (median, five cycles; range, one to eight cycles). The overall response rate was 24% (95% CI, 15% to 41%), including two complete responses (CR; 4%) and 10 partial responses (PR; 20%). Disease control (CR + PR + stable disease) was achieved in 67% of patients. The median times to disease progression and overall survival were 7 months (95% CI, 6.4 to 9.5 months) and 11 months (95% CI, 8.6 to 13.3 months), respectively. Of the 35 patients evaluated for clinical benefit response, 14 (40%; 95% CI, 24% to 58%) showed clinical benefit. Capecitabine was well tolerated. Treatment-related grade 3 and 4 adverse events were observed in only six patients (12%), and the most common events were diarrhea, hand-foot syndrome, and thrombocytopenia. One patient (2%) had an episode of angina, but no treatment-related deaths were reported.
CONCLUSION: Our findings suggest that capecitabine is effective and well tolerated in elderly patients with advanced CRC who are considered ineligible for combination chemotherapy.
INTRODUCTION
Colorectal cancer (CRC) is one of the most frequently encountered malignancies and is third behind breast and cervical cancer in women and fourth after lung, stomach, and prostate cancer in men.1 The prevalence of CRC increases significantly with age, with 40% of patients in Europe being older than 74 years of age at the time of initial diagnosis.2 Considering that approximately 25% of the population in industrialized countries is older than 70 years, the number of elderly patients with CRC is expected to increase significantly over the next two decades.
For more than 40 years, fluorouracil (FU) has been the mainstay of chemotherapy for advanced CRC. Recently, however, the topoisomerase I inhibitor irinotecan and the platinum compound oxaliplatin have shown efficacy as second-line single-agent therapy and as first-line therapy in combination with fluoropyrimidines. In large phase III trials, irinotecan in combination with FU-leucovorin and oxaliplatin in combination with FU-LV showed superior efficacy compared with FU-LV alone as first-line therapy.3-7 Although such combination regimens offer important improvements over FU-LV alone, they are often limited by high rates of toxicity,8,9 the inconvenience and discomfort of regular hospital visits for intravenous (IV) drug administration, and an increased associated risk of infection and thromboembolism.10-12 These issues are a particular problem in the elderly. Although the aging process is highly individualized, we considered 70 years of age as a chronologic cutoff for the onset of senescence because the rate of age-related changes increases steeply after this age.13 The progressive restriction in the functional reserve of various organ systems, the increasing prevalence of comorbid conditions, and the fear of greater susceptibility to side effects that negatively impact quality of life may be some of the factors that account for the reluctance to use chemotherapy in the elderly.14,15 Because the number of people older than 70 years included in clinical trials is small, the potential benefits and tolerability of combination chemotherapy in elderly patients remains unclear.
Capecitabine (Xeloda; Hoffmann-La Roche Inc, Nutley, NJ) is an orally administered fluoropyrimidine designed to deliver FU to tumor tissue.16,17 Capecitabine single-agent therapy has been shown to be highly effective as first-line treatment for metastatic CRC, demonstrating superior response rates and at least equivalent time to progression (TTP) and survival compared with FU-LV in two large, randomized, controlled phase III trials.18-20 An integrated analysis of safety from these trials, which included a total of 596 patients treated with capecitabine, also demonstrated a significantly lower rate of grade 3 and 4 diarrhea, stomatitis, nausea, and neutropenia but a higher rate of hand-foot syndrome with capecitabine.21 In the joint safety analysis, 51 patients were between 75 and 79 years of age, and only 13 patients were 80 years. Although a higher rate of adverse events was observed in the oldest patients, this could be attributable to the deterioration of renal function with age. A joint analysis of results from studies of irinotecan-FU-LV versus FU-LV3 and FU-LV versus capecitabine18 has also shown that administration of capecitabine single-agent therapy could be more cost effective than irinotecan-FU-LV in patients more than 65 years of age.22
The efficacy, favorable tolerability, and ease of administration of capecitabine make it ideal for use in both the general CRC population and in elderly patients. Consequently, the primary objective of this study was to determine the safety profile and to identify the possible predictive factors for toxicity when capecitabine single-agent therapy was administered in patients with advanced CRC who were 70 years.
PATIENTS AND METHODS
Patient Population
April 2002 to November 2002, 51 patients 70 years with recurrent or metastatic CRC were enrolled. All patients had measurable disease defined by the presence of at least one unidimensionally measurable lesion (Response Evaluation Criteria in Solid Tumors criteria)23 by computed tomography scan. Pleural effusion, ascites, osteoblastic lesions, or previously irradiated lesions were not accepted as measurable disease.
Patients who had received prior adjuvant FU-based chemotherapy were eligible if they had been disease-free for at least 6 months after the completion of therapy. Patients who had received radiotherapy were eligible if there was at least one measurable lesion outside the radiation field. Other inclusion criteria were as follows: Eastern Cooperative Oncology Group (ECOG) performance status 2; life expectancy of at least 3 months; determined as unsuitable for combination chemotherapy by their doctor or refusal of treatment by the patient; adequate hematologic function (granulocyte count 2 x 109/L and platelets > 100 x 109/L); adequate hepatic function (serum bilirubin < 1.25 x upper normal limit [UNL] and AST and ALT values < 2.5 x UNL in the absence of hepatic metastases or < 5 x UNL in the presence of metastasis); and adequate renal function (creatinine clearance 30 mL/min). All patients provided written informed consent according to local ethical committee directives.
Patients with operable metastatic disease were excluded from the study. Other exclusion criteria were as follows: clinically significant cardiac disease or myocardial infarction within the last 12 months; lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome; prior chemotherapy for advanced disease; known brain or meningeal metastases; and history of other malignancy, except basal cell carcinoma or adequately treated in situ cervical carcinoma.
Treatment Plan
The initial dose of capecitabine depended on the renal function of the patient, as determined by creatinine clearance. Patients with a creatinine clearance of more than 50 mL/min received capecitabine at 1,250 mg/m2 twice daily (2,500 mg/m2 total daily dose) for 2 weeks followed by 1 week of rest. In patients with a creatinine clearance of 30 to 50 mL/min, the dose of capecitabine was reduced to 950 mg/m2 twice daily (1,900 mg/m2 total daily dose). The dose of capecitabine was rounded to the next closest dose that could be administered using a combination of 500- and 150-mg tablets. The two daily doses of capecitabine were administered 12 ± 2 hours apart, 30 minutes after meals (breakfast and evening meal), with approximately 200 mL of water.
The Cockcroft-Gault formula24 was used to calculate the creatinine clearance between cycles. If clearance was less than 30 mL/min, treatment was interrupted. Cycles were repeated every 3 weeks for a minimum of three cycles per patient, unless disease progression was detected. Patients with a partial response or stable disease continued chemotherapy until progression or the development of unacceptable adverse events.
Patients were evaluated for adverse events before each cycle and graded according to WHO criteria.25 For hand-foot syndrome, the following grading system was used26: grade 1, numbness, dysesthesia, painless swelling, or erythema not disrupting normal activities; grade 2, painful erythema and/or swelling or symptoms affecting activities of daily living; and grade 3, moist desquamation, ulceration, blistering, and/or severe pain or symptoms making patients unable to work or perform activities of daily living. Treatment was continued at the same dose (without interruption or dose reduction) in case of grade 1 adverse events. Capecitabine dose reduction was not required after the first appearance of any grade 2 adverse events, although treatment was interrupted until the event had resolved to grade 0 or 1. Treatment was interrupted and the capecitabine dose was reduced by 25% in patients who experienced a second occurrence of a given grade 2 adverse event or any grade 3 event, and capecitabine dose was reduced by 50% for patients who experienced a third occurrence of a given grade 2 adverse event or the second occurrence of a given grade 3 adverse event. Treatment was discontinued in the case of grade 4 adverse events or if a given event occurred at grades 2 or 3 despite dose reduction to 50% of the original dose.
Pretreatment and Follow-Up Evaluation
A diagnostic work-up was performed within 3 weeks before the start of treatment and consisted of a complete clinical history, physical examination, blood analysis (hematology and complete biochemistry), and imaging studies as needed (chest x-ray, computed tomography of the chest, abdomen and pelvis, abdominal ultrasound, and bone scan). The Charlson comorbidity scale,27 and the Katz et al28 and Lawton29 Activities of Daily Living (ADL) indices were used in patient assessment. Patients' ECOG performance status and weight were also recorded. An ECG was performed in all patients before receiving study treatment. Symptom assessment, physical examination, and blood biochemistry were repeated before each treatment cycle. Tumor measurements were taken every three cycles or sooner if clinically indicated.
Response Criteria
Patients were evaluated clinically on an intent-to-treat basis at least every 3 weeks and radiographically every 9 weeks. The same evaluation modality was used throughout the study. Response Evaluation Criteria in Solid Tumors response guidelines were used,23 defining all responses after at least 9 weeks of therapy as follows: complete response (CR), partial response (PR), stable disease (SD), or progressive disease. We defined disease control as the sum of patients achieving a CR, PR, or SD. Confirmation of all responses was required after 4 weeks. TTP was estimated from the date of the first course of treatment to the date of the first documentation of disease progression. Survival was calculated by the same method from the date of the first cycle of treatment until the date of death or last known follow-up.
Clinical Benefit Response
An assessment of clinical benefit was determined from a composite of pain intensity, analgesic consumption, ECOG performance status, and the presence of anorexia and asthenia. The same doctor for each patient assessed ECOG performance status and symptoms before each chemotherapy cycle. Patients entered a pain stabilization run-in period to establish baseline measures. Pain was assessed with the Memorial Pain Assessment Card (MPAC).30 Asthenia and anorexia were assessed using a line-of-vision visual analog scale (VAS) of 0 to 100. In addition, patients' weight was measured at each visit. Patients were considered to be assessable for palliative benefits when they initially had one of the following signs or symptoms: an ECOG performance status 1, an MPAC score 20, baseline analgesic consumption of 10 morphine equivalents mg/d, score on the line-of-vision VAS for anorexia and/or asthenia of 20, or weight loss more than 10% during the previous 6 months.
Symptom improvement was defined as follows: an improvement of at least one score from baseline in ECOG performance status; 5% weight gain from baseline (patients with edema, ascites, or pleural effusion were excluded from this category); or an improvement of 50% from baseline in disease-related symptoms (pain, use of analgesics, anorexia, and asthenia) and analgesic consumption (measured weekly in morphine-equivalent milligrams). Each of these improvements had to be sustained for at least 4 weeks.31 Clinical benefit was defined as improvement in ECOG performance status without worsening of symptoms or weight loss, weight increase without worsening of ECOG performance status or symptoms, or symptom improvement without worsening of ECOG performance status.
Statistical Methods
The primary end point of the trial was to determine the safety profile of capecitabine. Secondary objectives were clinical benefit, TTP, and survival. Dose-intensity was calculated for each patient from the total dose of capecitabine administered during the entire course of treatment and expressed as the mean drug dose in mg/m2/wk. It was anticipated that 17% of patients would develop grade 3 or 4 toxicity.21 Therefore, 51 patients had to be included to estimate toxicity within a 20% maximum limit for the 95% CI. Univariate analysis was used to compare the rate of grade 3 and 4 adverse events according to age (70 to 79 years v 80 years), sex, creatinine clearance (< 50 mL/min v 50 mL/min), Charlson comorbidity scale (0 v 1), ECOG performance status (0 v 1), and Instrumental ADL (IADL) and ADL (independent v dependent). Wilcoxon's signed rank test (to compare the quantitative variables) and Fisher's exact test (to compare percentages) were used. Survival time and TTP were calculated using the Kaplan-Meier method.
RESULTS
Patient Characteristics
A total of 51 patients 70 years with advanced CRC were enrolled. The characteristics of the patients are listed in Table 1. Thirteen patients (25%) presented with metastases at the time of diagnosis, and in eight patients (16%), the primary tumor was not resected. The 39 remaining patients (76%) presented with secondary metastases to a previously resected tumor. Of these patients, 10 (26%) had received previous adjuvant chemotherapy, and eight (20%) had been treated with chemotherapy and radiotherapy.
Thirteen patients had previously refused treatment with combination chemotherapy. In the remaining patients, combination regimens were not used because of poor functional status (as defined by serious dependency in the ADL scale or in the IADL scale, n = 15; comorbidities, n = 5; and because of age older than 75 years, n = 18).
Comorbid conditions are listed in Table 2. When interpreting these results, it is important to note that the Charlson's scale only picks up serious conditions that have an impact on treatment decisions. Other less serious comorbid conditions, such as hypertension or gastric ulcers, are not included.
Treatment Duration
A total of 248 cycles of treatment were administered, with a median of five cycles per patient (range, one to eight cycles). Nine patients (18%) received less than three cycles of capecitabine; five patients (10%) received less than three cycles because of disease progression, two patients (4%) received less than three cycles because of adverse events, and one patient (2%) refused to continue treatment. Nevertheless, all of the patients enrolled were considered assessable for both efficacy and safety. Twenty-three patients (45%) experienced treatment delays during the study (14 patients for causes unrelated to the treatment, two because of neutropenia, and seven because of nonhematologic adverse events). The median dose intensity was 10.3 g/m2/wk, which is equivalent to 88% of the predicted dose intensity.
Tumor Response and Survival
In the intent-to-treat analysis, the overall response rate was 24% (95% CI, 15% to 41%), including two patients (4%) with a CR and 10 patients (20%) with a PR. Twenty-two patients (43%) maintained SD, and 17 patients (33%) had disease progression. Overall, disease control (CR + PR + SD) was achieved in 67% of the patients. There was no relationship between the rate of response and the location of metastases, ECOG performance status, ADL, IADL, or patient age.
The median TTP was 7 months (95% CI, 6.4 to 9.5 months; Fig 1). Median survival was 11 months (95% CI, 8.6 to 13.3 months; Fig 2), and the actuarial survival rate per year was 40%.
Clinical Benefit Response
Of the 51 enrolled patients, 35 were assessable for a clinical benefit response. The remaining 16 patients were not assessable because of the following: ECOG of 0, MPAC score less than 20, or VAS for anorexia and asthenia of less than 20. Clinical benefit responses are listed in Table 3. Overall, 14 patients (40%; 95% CI, 24% to 58%) had a clinical benefit. The median duration of clinical benefit was 4 months (95% CI, 2 to 8 months).
Safety
Generally, treatment was well tolerated. Twenty-eight patients (55%) experienced treatment-related adverse events, the majority of which were grade 1 to 2 in severity. The main treatment-related adverse events were gastrointestinal and hematologic (Fig 3). Six patients (12%) experienced treatment-related grade 3 and 4 adverse events; one patient (2%) had nausea and vomiting, three (6%) had diarrhea, three (6%) had hand-foot syndrome, one (2%) had neutropenia, and two (4%) had thrombocytopenia. One patient (2%) experienced one episode of angina. No treatment-related deaths were reported during the study.
In an exploratory univariate analysis, we detected no relationship between the presence of grade 3 and 4 adverse events and patient age (70 to 79 years v 80 years), sex, IADL, ADL, ECOG, comorbidity, renal function, or capecitabine dose (950 mg/m2 twice a day or 1,250 mg/m2 twice a day). However, it should be noted that, because of the low rate of grade 3 and 4 adverse events and the small sample size, the study did not have sufficient power to definitely rule out any such relationships.
DISCUSSION
Age clearly represents a barrier to the inclusion of patients in clinical trials of new cancer therapies.32,33 In the most relevant studies performed in patients with CRC, less than 20% of patients were 70 years.34 In addition, the number of patients older than 75 years is low, suggesting that these patients are carefully selected and are not necessarily representative of this age group. Therefore, extrapolating the results from clinical trials including young patients or selected elderly populations to groups over the age of 75 years is problematic.
In the current study, we evaluated capecitabine as first-line therapy in elderly patients with advanced CRC who were considered ineligible for combination chemotherapy. The patients included in the study were typical of an elderly population because the proportion of patients with rectal cancer was higher than normal (47%), which tends to be the case in older patients. Furthermore, the fact that only 46% of the patients potentially eligible for adjuvant chemotherapy had received prior adjuvant chemotherapy and adjuvant treatment was not administered to 34% of the patients with stage III disease provides further proof that elderly patients are often undertreated in the adjuvant setting.
In our study, capecitabine produced a response rate of 24%, a median TTP of 7 months, and a median survival of 11 months. These findings are similar to those reported from previous studies of capecitabine as first-line therapy in patients of all ages with advanced CRC.20 Although TTP in our study seemed to be longer compared with previously published findings with capecitabine single-agent therapy or similar to the capecitabine-based combinations,20,35,36 this may have been the result of tumor evaluation every 9 weeks instead of every 6 weeks as in previous studies. In contrast, median overall survival time was a little shorter than reported for capecitabine single-agent therapy in the first-line setting. However, this might be explained by the baseline characteristics of our elderly patients and the fact that they were ineligible to receive combination chemotherapy, which would be expected to lead to a median survival time of more than 12 months.
The safety of capecitabine in the current study was favorable, with only 12% of patients developing grade 3 and 4 adverse events. This is likely to be attributable to the adjustment of the dose based on patients' creatinine clearance.21,37 These results are similar to those of another study in which capecitabine at a dosage of 1,000 mg/m2 twice daily led to a grade 3 and 4 adverse event rate of 14% in elderly and less fit patients with advanced CRC.38 Alternatively, the fact that 35% of the patients enrolled onto the study had received prior chemotherapy with FU-LV in the adjuvant setting with a good tolerance could have introduced a bias in the sense that these patients might also have good tolerance to capecitabine. Importantly, we did not find any correlation between the occurrence of adverse events and baseline characteristics that are normally associated with increased toxicity, such as female sex,39 the presence of comorbidities,15 performance status, and so on. In particular, excessive comorbidity has been reported to be associated with increased toxicity in elderly patients.15 Despite 80% of the patients in our study suffering from some comorbidity and 29% of the patients being 80 years, we did not detect any higher rate of adverse events in these patients. However, it is necessary to note that the power of the study, because of the low number of patients with severe adverse events, might be insufficient to detect such a relationship.
In addition to its good antitumor efficacy and favorable tolerability, oral administration of capecitabine avoids the possible complications and discomfort of IV therapy.8-12 Furthermore, compared with weekly or biweekly IV dosing schedules, home-based administration of capecitabine on days 1 to 14 every 3 weeks reduces the need for hospital visits, which may be inconvenient in elderly patients who require assistance from a relative or caregiver. Nevertheless, it is still important for patients to receive good-quality educational materials and to have regular phone contact with their nurse or physician. Patients with dependency for the daily activities of life may still require a caregiver who takes full responsibility of administering treatment and the early detection of adverse events.
Combination chemotherapy is currently considered to be more effective than single-agent therapy in patients with advanced CRC, and therefore, it is important to consider to what extent elderly patients should receive combination regimens. Because the elderly represent a heterogeneous population, treatment should be individualized based on the possible risks and benefits expected in each patient. In addition, it is important to take into account the patient's wishes; although older patients are often as willing to chose combination chemotherapy as their younger counterparts, the elderly require a greater survival advantage before choosing a more toxic regimen over a less-aggressive alternative.40 When choosing a combination regimen, it is important to consider that the patient's age can affect the pharmacokinetics of certain drugs like irinotecan.34 Indeed, a higher rate of adverse events was detected in a study of irinotecan in patients 65 years compared with patients younger than 65 years (rate of grade 3 and 4 diarrhea, 39% v 19%, respectively),41 although this has not been confirmed in other studies.42 An increase in grade 3 and 4 diarrhea has also been reported when oxaliplatin is administered in combination with FU-LV in patients older than 65 years (18% v 8% in patients aged 65 years).5 Nevertheless, physiologic factors rather than actual age govern treatment decisions, and there is still a huge population of patients who are unable to tolerate combinations of cytotoxic agents.
Clearly, as supported by the results of our study, capecitabine single-agent therapy is an important therapeutic option in elderly patients who are ineligible for combination chemotherapy. The availability of new biologic therapies, such as bevacizumab (Avastin; Genentech, South San Francisco, CA), which has already shown promising activity and good tolerability in combination with FU in advanced CRC and with capecitabine in advanced breast cancer,43,44 might be expected to improve outcomes without increasing toxicity in elderly patients. A study combining capecitabine with bevacizumab in elderly patients with advanced CRC is an interesting possibility for the future. The apparent lack of sufficient adjuvant therapy for elderly patients with early-stage colon cancer is another important area where a drug like capecitabine, which has a proven safety profile in the metastatic and adjuvant settings,45 can improve outcomes in an increasingly elderly patient population.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by Hoffmann-La Roche Inc, Nutley, NJ.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Ferlay J, Bray F, Pisani P, et al: GLOBOCAN 2000: Cancer Incidence, Mortality and Prevalence Worldwide, Version 1.0. Lyon, France, International Agency for Research on Cancer CancerBase No. 5, IARCPress, 2001
Gatta G, Faivre J, Capocaccia R, et al: Survival of colorectal cancer patients in Europe during the period 1978-1989: EUROCARE Working Group. Eur J Cancer 34:2176-2183, 1998
Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan Study Group. N Engl J Med 343:905-914, 2000
Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomized trial. Lancet 355:1041-1047, 2000
de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000
Giacchetti S, Perpoint B, Zidani R, et al: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18:136-147, 2000
Grothey A, Deschler B, Kroening H, et al: Phase III study of bolus 5-fluorouracil (5-FU)/folinic acid (FA) (Mayo) vs weekly high-dose 24h 5-FU infusion/FA + oxaliplatin (OXA) (FUFOX) in advanced colorectal cancer (ACRC). Proc Am Soc Clin Oncol 21:129a, 2002 (abstr 512)
Ledermann JA, Leonard P, Seymour M: Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer. N Engl J Med 345:145-146, 2001
Rothenberg ML, Meropol NJ, Poplin EA, et al: Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: Summary findings of an independent panel. J Clin Oncol 19:3801-3807, 2001
Clark DR, Raffin TA: Infectious complications of indwelling long-term central venous catheters. Chest 97:966-972, 1990
Prandoni P, Bernardi E: Upper extremity deep vein thrombosis. Curr Opin Pulm Med 5:222-226, 1999
Verso M, Agnelli G: Venous thromboembolism associated with long-term use of central venous catheters in cancer patients. J Clin Oncol 21:3665-3675, 2003
Balducci L, Extermann M: Cancer and aging: An evolving panorama. Hematol Oncol Clin North Am 14:1-16, 2000
Simmonds PD, Best LY: Should chemotherapy be used as a treatment of advanced colorectal carcinoma (ACC) in patients over 70 years age Contra. Eur J Cancer 35:1640-1649, 1999
Balducci L, Extermann M: Management of cancer in the older person: A practical approach. Oncologist 5:224-237, 2000
Miwa M, Ura M, Nishida M, et al: Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34:1274-1281, 1998
Schüller J, Cassidy J, Dumont E, et al: Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 45:291-297, 2000
Hoff PM, Ansari R, Batist G, et al: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 19:2282-2292, 2001
Van Cutsem E, Twelves C, Cassidy J, et al: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: Results of a large phase III study. J Clin Oncol 19:4097-4106, 2001
Van Cutsem E, Hoff PM, Harper P, et al: Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: Integrated efficacy data and novel analyses from two large, randomized, phase III trials. Br J Cancer 90:1190-1197, 2004
Cassidy J, Twelves C, Van Cutsem E, et al: First-line oral capecitabine therapy in metastatic colorectal cancer: A favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann Oncol 13:566-575, 2002
Vincent M, Jonker D, Lane Ilersich A: A model for assessing cost-effectiveness of metastatic colorectal chemotherapy. Proc Am Soc Clin Oncol 20:211b, 2001 (abstr 2595)
Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000
Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41, 1976
World Health Organization: WHO Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, World Health Organization, WHO offset publication No. 48, 1979
Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17:485-493, 1999
Charlson ME, Pompei P, Ales KL, et al: A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis 40:373-383, 1987
Katz S, Ford AB, Moskowitz RW, et al: Studies of illness in the aged: The index of ADL—To standardized measure of biological and psychosocial function. JAMA 185:914-919, 1963
Lawton MP: Scales to measure competence in everyday activities. Psychopharmacol Bull 24:609-614, 1988
Fishman B, Pasternak S, Wallestein SL, et al: The Memorial pain assessment card: A valid instrument for the evaluation of cancer pain. Cancer 60:1151-1158, 1987
Cocconi G, Cunningham D, Van Cutsem E, et al: Open, randomized multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. J Clin Oncol 16:2943-2952, 1998
Yee KW, Pater JL, Pho L, et al: Enrollment of older patients in cancer treatment trials in Canada: Why is age a barrier J Clin Oncol 21:1618-1623, 2003
Lewis JH, Kilgore ML, Goldman DP, et al: Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol 21:1383-1389, 2003
Honecker F, Kohne CH, Bokemeyer C: Colorectal cancer in the elderly: Is palliative chemotherapy of value Drugs Aging 20:1-11, 2003
Shields AF, Zalupski MM, Marshall JL, et al: Treatment of advanced colorectal carcinoma with oxaliplatin and capecitabine: A phase II trial. Cancer 100:531-537, 2004
Cassidy J, Tabernero J, Twelves C, et al: XELOX (capecitabine plus oxaliplatin): Active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 22:2084-2091, 2004
Gieschke R, Burger HU, Reigner B, et al: Population pharmacokinetics and concentration-effect relationships of capecitabine metabolites in colorectal cancer patients. Br J Clin Pharmacol 55:252-263, 2003
Vincent M, Jonker D, Kerr I, et al: Reduced-dose capecitabine monotherapy in older or less fit patients with advanced colo-rectal cancer (A CR Ca). Proc Am Soc Clin Oncol 22: 323, 2003 (abstr 1297)
Macdonald JS: Vive la difference: Sex and fluorouracil toxicity. J Clin Oncol 20:1439-1441, 2002
Yellen SB, Cella DF, Leslie WT: Age and clinical decision making in oncology patients. J Natl Cancer Inst 86:1766-1770, 1994
Rothenberg ML, Cox JV, DeVore RF, et al: A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer 85:786-795, 1999
Rougier P, Mitry E, Cunningham D, et al: Is age a prognostic factor of toxicity and efficacy in patients (pts) with metastatic colorectal cancer (MCRC) receiving irinotecan in combination with 5FU/folinic acid (FA). Proc Am Soc Clin Oncol 22: 267, 2003 (abstr 1072)
Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al: Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60-65, 2003
Miller KD, Chap LI, Holmes FA, et al: Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792-799, 2005
Scheithauer W, McKendrick J, Begbie S, et al: Oral capecitabine as an alternative to i.v. 5-fluorouracil-based adjuvant therapy for colon cancer: Safety results of a randomized, phase III trial. Ann Oncol 14:1735-1743, 2003(Jaime Feliu, Pilar Escude)